Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Epidemiologic studies showed that inorganic arsenic exposure induced lung, skin, liver, and bladder cancers. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. Arsenic is also strongly linked to non-malignant lung vascular diseases. Our preliminary results showed that exposure of lung epithelial cells to arsenic produced high levels of reactive oxygen species (ROS). Arsenic induced AKT and ERK1/2 activation, and increased HIF-1 expression and VEGF transcriptional activation. We hypothesize that arsenic induces carcinogenesis through ROS signaling, which in turn regulates PI3K, AKT, ERK1/2, and HIF-1. To test this hypothesis, we will perform the following two aims. In Aim 1, we will identify which species of ROS induced by arsenic and the mechanism of ROS generation in the lung epithelial cells, then determine whether arsenic regulates PI3K, AKT, and ERK activation through ROS generation in the cells. Aim 2 will determine the role of arsenic in inducing tumorigenesis, and whether arsenic induces tumorigenesis through ROS production, PI3K, AKT, ERK1/2, and HIF-1 expression. We will study signaling pathways and molecules that regulate the progression of arsenic-inducing tumor growth. After we learn the effects and the underlying mechanism of arsenic in inducing carcinogenesis, we will be able to develop mechanism-based interventions to prevent carcinogenesis induced by arsenic in the future. PUBLIC HEALTH RELEVANCE: Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Arsenic is known carcinogen for inducing human cancer. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. In this study, we plan to study the roles and mechanism of arsenic in inducing signaling pathways and molecules that are associated with carcinogenesis and tumorigenesis, and to analyze these signaling molecules in arsenic-inducing tumorigenesis. This information will be useful for us to develop mechanism-based interventions to prevent arsenic-inducing carcinogenesis in the future.